The primary goal of this CEBRA grant is to utilize a novel integrated genomics and metabolomics approach to develop clinically relevant and readily available endocannabinoid system (ECS) biomarkers of overweight disorders that will improve risk assessment and selection of ECS-based disease modifying therapies for affected individuals. This project is directly related to public health because overweight (OW) and obesity (OB) are considered to be one of the most serious, pervasive and costly global public health problems of the twenty-first century. Although the causes, risk factors and complications are thought to involve many complex genetic and environmental factors, the endocannabinoid system has recently been identified as playing a major role in the regulation of food intake and fat metabolism and, consequently, in the development of OW and OB. The objective is to identify and validate circulating ECS biomarkers that include genetic mutations in the main endocannabinoid inactivating enzymes (FAAH and MAGL) and metabolomic profiling of fatty acid amide bioactive lipids that are elevated in the circulation of OW and OB subjects compared to case control populations. Integration of the genetic and metabolomic biomarker findings will enable the development of an ECS risk profile for use in diagnostic assessments, disease staging and likelihood of response to endocannabinoid antagonist therapies such as Rimonabant (Acomplia). This project addresses an urgent need by developing circulating endocannabinoid biomarkers that may be used from basic research to the clinic. Our working hypothesis is that subjects with genetically reduced FAAH or MAGL activity and heightened levels of endocannabinoid tone would be particularly amenable to the weight-lowering effects of Rimonabant. Since obesity disorders are thought to be a manifestation of a type of addictive behavior with abnormal reward and craving responses, the endocannabinoid biomarkers developed through this CEBRA will be directly relevant not only to the expanding obesity epidemic but may also be relevant to drug addiction behaviors. This project will significantly accelerate future obesity research and will support the development of more novel ECS-based treatment options as a result of increased clinical and investigational use of these endocannabinoid biomarkers for overweight and obesity worldwide. This cutting edge basic research project is designed to find new markers of overweight and obesity in the blood of people with these disorders. We will measure the body's own circulating Cannabis-like chemicals in patients and find gene abnormalities that are risks for overweight and obesity. Our findings will be used to improve public health by helping people with the choice of the best treatment for their obesity problems, find other family members at risk of becoming obese and by the discovery of risk factors that could produce new obesity treatments through more laboratory research. [unreadable] [unreadable] [unreadable]